Ethics in a new era Microbicides 2012 Preconference Bridget Haire

Ethical issues in research Balance of risks of benefits Fairness Consent – Voluntary – Sufficient understanding – No coercion Promote justice, avoid exploitation – Reasonable likelihood that the trial community will eventually derive benefit – Risks not disproportionate or unreasonable

Community role in ethical research process Make the research better Get the best deal possible for participants* and the local community (risk/benefit balance, fairness, consent, no exploitation) Communicate effectively with research team about issues that affect the research process, outcomes and participants Communicate with and listen to the wider community about the research

What’s the new era? Positive trial results: can we still use placebos? Adherence as critical: supporting it, measuring it, communicating honestly about it ‘Futility’ results (FemPrEP, Voice) – Stopping rules: when should a trial be stopped for futility? – Are IIB trials still useful?

Study Effect size (CI) Medical male circumcision (MMC) ( Orange Farm, Rakai, Kisumu) 57% (42, 68) Prime-boost HIV Vaccine (Thai RV144) 31% (1, 51) Efficacy 0% % TDF/FTC oral-PrEP in MSM (iPrEx, Grant et al 2010) 44% (15, 63) 1% tenofovir gel (Caprisa 004, Karim et al.) 39% (6, 60) Slide: Robin Shattock IAS Plenary Rome 2011 Immediate ART for positive Partners (HPTN052) 96% (82, 99)* TDF/FTC oral-PrEP in heterosexuals ( TDF2, CDC) TDF oral-PrEP in serodiscordant Partner (Partners PrEP) 63% (22, 83)* TDF/FTC oral-PrEP in serodiscordant Partner (Partners PrEP) 62% (34, 78)* 73% (49, 85)* New biomedical intervention strategies 1% tenofovir gel (Caprisa 004, Karim et al.)

When should new interventions be added to prevention package? If the method been recommended by international bodies or adopted nationally But also if: – the evidence is strong AND – the intervention has shown efficacy in the relevant population; AND – if provision is feasible.

If the evidence is strong… Statistically significant (P = <0.05) Effect size is substantial (lowest end of the confidence interval needs to big enough to have an impact) More than one trial, or one trial with a very strong result Not entirely black and white, and subject to arguments about specific situations

Relevant populations Route of exposure (vagina/penis, rectum, intravenous) Might extrapolation be reasonable in some instances?

Is provision feasible? What are the barriers – regulatory, cost- associated, manufacturing issues? Cost associated issues might be resolvable through drug donations Regulatory issues may be resolvable through advocacy (or maybe not) Manufacturing issues may be impossible to solve short-term

When should a new intervention not be added? When there are safety issues regarding drug- drug interactions When the addition of a new intervention would compromise the ability of the trial to answer the relevant question (Is the trial addressing a relevant question?)

Grey areas Ipergay- French trial of PrEP in gay men comparing intermittent PrEP with placebo Issues – Continuous PrEP shown modestly effective in iPrEX (44%, but higher in good adherers) – Proof-of-concept in Partners PrEP and TNF2 (Botswana), though with penile exposure – BUT not approved for prevention (yet) anywhere

ASPIRE – more grey Vaginal ring that delivers the ARV dapivrine Ph III trial of 3476 randomised to active ring or ring with placebo Positive trial results that should be considered HPTN052 (early treatment of positive partner), CAPRISA 004 (tenofovir gel) Partners PrEP, TNF 2 (PrEP) Negative results FemPrEP, VOICE

Vaginal rings

Issue in ASPIRE PrEP could not be added to both arms, due to potential drug/drug interactions Head-to-head against PrEP or tenofovir gel? Early treatment offer for HIV positive partners of participants (applying HPTN052 lessons)?

IIB Trials/Stopping rules Both FemPrEP and VOICE were designed so that if a product was ineffective at certain time points, that arm of the trial was stopped Is this useful? Smaller trials have less power to give an answer Should trials be stopped for futility?

Ethics sessions at M2012 Standard of Prevention – Monday 11am Social and ethical issue in HIV Prevention – Monday 2 pm Beyond the Trial: ethical and operational challenges for post-trial access– Wednesday 11am